EP2237767A1 - Phenylephrine pharmaceutical formulations and compositions for transmucosal absorption - Google Patents

Abstract

Pharmaceutical compositions comprising phenylephrine or a pharmaceutically acceptable salt thereof and methods for administering the pharmaceutical compositions wherein the composition is formulated for systemic absorption of phenylephrine that avoids first pass metabolism. The compositions of the invention are formulated to be applied to oral mucosa of an animal to allow for enhanced systemic delivery of therapeutically active form of phenylephrine.

Description

Phenylephrine Pharmaceutical Formulations and Compositions for

Transmucosa! Absorption

BACKGROUND OF THE INVENTION

Identification or discussion of any reference in this section or any part of this specification shall not be construed as an admission that such reference is available as prior art to the present application.

Oral administration is the most preferred route for systemic pharmaceutical administration. However, oral administration of some pharmaceutical agents results in extensive pre-systemic metabolism of the agents as they undergo hepatic first pass metabolism and enzymatic metabolism within the gut wall. This extensive pre-systemic metabolism dramatically reduces the effective amount of pharmaceutical agent ultimately absorbed into the blood stream and available for therapeutic action. Transmucosal routes of drug delivery (i.e., the mucosal linings of the nasal, rectal, ocular, and oral cavity) offer advantages over oral administration of pharmaceutical agents that avoid the first pass effect and pre- systemic elimination within the gut wall, and speed absorption into the blood stream. Phenylephrine undergoes extensive pre-systemic metabolism, with a majority of the metabolism taking place within the enterocytes of the gastrointestinal tract. (See, e.g., Ibrahim, K.E. et al., Journal of Pharmacy and Pharmacology 35, 144-147 (1983)). Phenylephrine is metabolized by Phase I and Phase M enzyme systems, mainly monoamine oxidase and suflotransferase, respectively. Ibrahim and coworkers measured the metabolism of phenylephrine after oral and inhalation administration and found four main metabolites were excreted in urine, unconjugated m-hydroxymandelic acid, sulfate conjugate of m- hydroxyphenylglycol, sufate conjugate of phenylephrine and glucuronide conjugate of phenylephrine. The ratios of the phenyephrine metabolites differed depending on the route of administration, yet neither route demonstrated prolonged plasma ;eve?s of parent (unmetabofeed) phenylephrine. Another study reported that oral administration of Comhist® tabtets containing 10 or 20 mg of phenylephrine showed concentrations of parent phenylephrine in plasma were below the limit of quantitation of 2 ng/ml. (Gumbbrr, K. An investigation of Pharmacokinetics of Phenylephrine and its Metabolites in Humans. In Pharmaceutical Sciences, p. 216 (1993)). U.S. Patent Application No. 11/756,881 , filed June 1 , 2007, describe formulations that deliver phenylephrine and pharmaceutically acceptable salts thereof directly to the colon, avoiding pre-systemic metabolism. The application demonstrates that these formulations allow for systemic absorption of increased levels of parent phenylephrine compound resulting in demonstrable blood levels of parent phenylephrine for up to several hours.

Although the nasal, recta! and ocular mucosa offer certain advantages, the marginal patient acceptability renders them reserved for local applications rather than systemic drug administration. In particular, the potential irritation and the irreversible damage of the nasal cavity from chronic application make it less appealing as a method of administering several dosages as needed for effective systemic administration of phenylephrine. Alternatively, transdermal and oral mucosal delivery provide a highly acceptable administration route for chronic treatments. The oral mucosa is relatively permeable with a rich blood supply and demonstrates short recovery times after stress or damage, (Yajaman S., et al. J. Controlled Release. 114:2006, 15-40; Rathbone, MJ. and Hadgraft, J., Int. J.

Pharm,, 74:9-24, 1991; Squier, C.A., Crit. Rev, Oral Biol Med., 2:13-32, 1991. 15. Squier, C). The virtual lack of Langerhans ceils makes the oral mucosa tolerant to potential allergens. (Harris, D. and Robinson, J. R., J. Pharm, Set.._. 81 :1 -10, 1992) Oral transmucosal drug delivery also bypasses liver first pass metabolism and avoids pre-systemic elimination in the gastrointestinal tract.

Thus, a composition that would allow for substantia! systemic administration of unmetabolized phenylephrine would be useful. Further, a composition that allowed for prolonged administration of unmetabolized phenylephrine would be useful. Further orally administered phenylephrine compositions which avoid the metabolic issues associated with oral systemic administration would be useful. These and other objectives are provided by the invention described and claimed herein. Alt references cited herein are hereby incorporated in their entirety into the subject application,

SUMMARY OF THE INVENTION

This invention provides a pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition is formulated to be applied to oral mucosa to allow for enhanced systemic absorption of therapeutically active form of phenylephrine.

This invention further provides a pharmaceutical composition suitable for sublingual systemic administration of phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition allows for systemic absorption of phenylephrine from the floor of the mouth, This invention also provides a pharmaceutical composition suitable for buccal systemic administration of phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition allows for absorption of phenylephrine from the buccal mucosa.

This invention also provides a method of systemicatly administering phenylephrine which comprises contacting oral mucosa with a pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition allows for release of phenylephrine to oral mucosa.

This invention further provides a dissolvable composition comprising phenylephrine distributed within an aqueous soluble base material, wherein the composition Is provided as a strip for inter-oral administration of phenylephrine to the mucus membranes of the mouth of a human or animal subject.

This invention also provides a bioerodible, water-soluble, carrier device comprising a non-bioadhesive backing layer, a bioadhesive layer and a composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, wherein the bioadhesive layer is formulated to adhere to a mucosa! surface of a mamma! and provides sustained delivery of the composition. This invention further provides a composition for buccal or sublingual application comprising a distribution of multilayer microparticles in a base, wherein phenylephrine or a pharmaceutically acceptable salt thereof is adsorbed within the layers of the microparticles so as to be progressively released over time to the buccal or subungual mucosa.

This invention also provides a drug delivery device adapted for application sublinguaHy of the oral cavity for fast release thereon of a composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, said device comprising a body having the composition distributed therein and having a size and shape suitable for sublingual application

This invention also provides a pharmaceutical formulation adapted for application and adherence to the mucosa of the oral cavity for sustained release thereon of a composition comprising phenylephrine or a pharmaceutically acceptable salt thereof wherein the composition is in the form of a liquid or semisolid.

BRIEF DESCRIPTION QF THE FIGURES

Figures 1 A and 1 B: graphs showing calcium flux studies demonstrating that phenylephrine {■) but not 3-hydroxymandelic acid (♦) increases intracellular calcium in Ot_{1 a} and cti_b expressing CHO cells.

Figures 2A and 2B: graphs showing receptor binding studies demonstrating that phenylephrine (■) but not 3-hydroxymande!ic acid (♦) inhibits binding of ³H- prazosin to α_1a and oti_b CHO cell membranes.

Figures 3A_» 3B, and 3C: graphs showing receptor binding studies demonstrating that phenylephrine (■) but not 3-hydroxymandelϊe acid (A (3A, 3B)₁ ♦ (3C)) stimulates [³⁵SJ-GTPγS binding to α_2a and α₂b and a_2c CHO cell membranes.

Figures 4A, 4B₅ and 4C: graphs showing receptor binding studies demonstrating that phenylephrine (■) but not 3-hydroκyrnandeisc acid (4 ) inhibits [³Hj-UKI 4304 binding to α_2a and α₂b and α_2c CHO cell membranes. Figures 5A and 58: graphs showing calcium flux studies demonstrating that phenylephrine sulfate (A) induces minimal intracellular calcium increases in cti_a and αi_b expressing CHO cells. (■ = PE ; • = Theoretical 0.1% PE)

Figures 6A and 6B: graphs showing receptor binding studies demonstrating that phenylephrine (■) but not PE sulfate (A) inhibits binding of ³H-prazosin to oci_a and αi_b CHO ceil membranes. (• = Theoretical 0.1 % PE)

Figures 7 A, 7B, and 7C: graphs showing receptor binding studies demonstrating that phenylephrine (a) but not PE sulfate (A) stimulates [³⁵S]-GTPγS binding to α_2a and α₂b and α_2c CHO cell membranes. {♦ = Theoretical 0.1 % PE)

Figures 8A, 8B, and 8C: graphs showing receptor binding studies demonstrating that phenylephrine (■) but not PE sulfate ( A ) inhibits [³H]-UKI 4304 binding to α_2a and α_2b and α_2c CHO cell membranes. (• = Theoretical 0.1% PE)

Figures 9A and 9B: graphs showing calcium flux studies demonstrating that PE glucuronide (A) induces intracellular calcium increases in cti_a and αi_b expressing CHO cells consistent with level of contaminating phenylephrine. (■ = PE; • =

Theoretical 0.28% PE)

Figures tOA and 1OB: graphs showing receptor binding studies demonstrating that phenylephrine (■) but not PE glucuronide (A) (batch 2) inhibits binding of ³H- prazosin to α_1a and otib receptors (CHO cell membranes).

Figures 11 A, 11 B_» 11C: graphs showing receptor binding studies demonstrating that phenylephrine (■) but not PE glucuronide (T) (batch 2) stimulates [³⁵S]- GTPγS binding to α_2a and α_2b and α_2c CHO cell membranes.

Figures 12 A, 12B, and 12C: graphs showing receptor binding studies demonstrating that PE glucuronide ( A ) weakly inhibits binding of [³HI-UKI 4304 to «29, α₂b, and Oc₂₀ receptors (CHO cell membranes) consistent with level of contaminating phenylephrine. (■ = PE; • = Theoretical 0.28% PE)

DETAILED DESCRIPTION The subject invention provides a pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition is formulated for enhanced systemic absorption of phenylephrine that avoids first pass metabolism. In certain embodiments, the compositions of the invention are formulated to be applied to oral mucosa of an animal, human or otherwise, to allow for enhanced systemic delivery of therapeutically active form of phenylephrine, and thus optimize systemic exposure of a therapeutically active form of phenylephrine, by by-passing prβ-systemic metabolism.

As used herein a pharmaceutically acceptable salt of phenylephrine includes but is not limited to phenylephrine hydrochloride, phenylephrine bitartrate, phenylephrine tannate, etc. In one preferred embodiment, the pharmaceutically acceptable salt of phenylephrine is phenylephrine hydrochloride.

The term "unmetabolized phenylephrine" means Phenylephrine that has not been biotransformed by Phase i or Phase Il enzymes systems, or any other enzyme system, into a new chemical entity since entering the body of a subject except for the release of free base, i.e. Phenylephrine that has not been conjugated by a sulfotransfβrase or a UDP-glucuronsyltransferase enzymes, or chemically altered by any enzyme system in the body of a subject, including enzyme systems of microbial organisms. Unmetabolized phenylephrine exhibits therapeutic activity(ies). "Unmetabolized phenylephrine" does not include phenylephrine that was at one time inactivated by conjugation but was later unconjugated and is not therapeutically active. The term "enhanced systemic absorption of therapeutically active form of phenylephrine" as used herein refers to the increased amount of therapeutically active chemicai form of the administered phenylephrine, i.e., unmetabolized phenylephrine, absorbed into the systemic circulation and distributed to the body tissues, often characterized as area under the plasma concentration versus time curve, as compared to non-oral mucosal drug delivery forms. The term "pre-systemic modification" as used herein in connection with phenylephrine means modification of phenylephrine before phenylephrine is taken up into the bloodstream and thus into the plasma. Pre-systemic modification excludes modification of phenylephrine by the liver or within the bloodstream, As used here, the term "systemic oral mucosa! delivery" means administration to mucosal membranes within the oral cavity for systemic uptake. The compositions and methods of the invention described herein are designed to take advantage of administration to the non-keratinized epitheSia, such as found in the mucosa of the soft palate, the floor of the mouth and the buccal mucosa which are considerably more permeable to water and other small molecules compared to keratinized epithelia, In particular, oral mucosa! delivery is meant to include sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, as well as buccal delivery, which is drug administration through the mucosal membranes lining the cheeks {buccal mucosa). The permeability of oral mucosae found to be in between that of the epidermis and intestinal mucosa. In general, the permeabiiities of the oral mucosae decrease from the sublingual to buccal, and buccal to palatal region. The sublingual mucosa is comparatively more permeable and rapid absorption leads to acceptable bioavailabilities of many drugs, and is convenient, accessible, and generally well accepted (Harris, D. and Robinson, J. R., Drug delivery via the mucous membranes of the oral cavity, J. Pharm. ScL, 81 :1 -10, 1992). The subject invention contemplates administration of phenylephrine to these regions of the oral mucosa that will allow for similar systemic uptake of parent phenylephrine. A "dosage" or "dose" as used herein means the amount of a pharmaceutical composition comprising therapeutically active agent(s) administered at a time. "Dosage" or "dose" includes administration of one or more units of pharmaceutical composition administered at the same time.

"AUC^1* as used herein means, for any given drug, the "area under the concentration-time curve" from dosing or activation of the drug to a time point, calculated by the trapezoidal rule. AUC is a parameter showing the cumulative plasma concentration of a drug over time, and is an indicator of the total amount and availability of a drug in the plasma. ¹¹AUCo-C is defined as AUC for any value of time (t) up to 24 hours, In a preferred embodiment, t is 24 hours (referred to herein as AUCo-24). "AUC₀. -" is defined as calculated AUC extrapolated to infinity. AUCo- « is calculated as equal to AUC₀-_t + Ct/ Az, wherein Ct is the concentration at 24 hours and Kz is the terminal or elimination rate constant. Terminal or elimination rate constant Az is determined from the siope of the drug concentration-time curve using linear regression on terminal data points of the curve. "Relative AUC₀/ is defined as the percentage of the AUCo-_t value of unconjugated phenylephrine relative to the AUC_Q-_t value for the total phenylephrine in the plasma of the subject from a dosing regimen.

Pharmaceutical Compositions

The compositions of the invention can take on any of several forms suitable for oral administration of pharmaceutical compositions including liquid, solid or semi-solid.

Liquid forms can be those suitable for spraying from a pump spray or pressurized spray device such as an aerosol spray. Liquids can also be delivered to the oral mucosa from a solid carrier such as a capsule that can be opened and its contents emptied into the mouth. For example, U.S. Pat. Nos. 6,676,931 6,969,508, 6,767,925 disclose liquid formulations that deliver an active agent to the mouth for absorption through the oral mucosa, for example by spraying. Solid forms encompass all forms that are devised to be inserted into the mouth and either masticated or allowed to dissolve to release a pharmaceutical agent and include, but are not limited to, tablets, capsules, gums, films, lozenges, discs, spheres, and microspheres. For example, U.S. Patent Nos. RE 33,093 and 6.072,100. and 6375963 describe bioadhesive hot-melt extruded films for intra- oral drug delivery and the processing thereof. U.S. Patent No. 6,596,298 describes orally dissolving films with no mucoadhesive properties. U.S. Patent No. 6,284,264 describes mucoadhesive orally dissolving films. U.S. Patent No. 4,755,389 discloses hard gelatin capsule filled with a chewable composition containing an ingredient for buccal absorption. U.S. Patent No. 5,437,872 describes pharmaceutical tablet and lozenge forms providing controlled and sustained release of pharmaceutical agents. Such forms can also include forms referred to as fast dissolve, fast melt, and flash melt solid forms. For example U.S. Patent No. 6,723,348 describes fast dissolving tablets that disintegrate in the buccal cavity upon contact with saliva by formation of an easy-to-swaliow suspension. U.S. Patent Nos, 5,464,632, 6,106,861 , and 6,656,492 and PCT Published applications VVO 00/27357 and WO00/51568 describe fast dissolving tablet formulations where the active ingredient is in the form of orally disintegratable tablet containing coated microcrystals or coated microgranules.

Semi-soiid forms include, but are not limited to, chewing gums, viscous liquids, ointments, gels and hydrogel systems. For example, U.S. Patent Nos. 7,078,052, 6,773,716 and 6,558,692 disclose pharmaceutical chewing gum formulations for delivering active agents to the oral mucosa.

In certain embodiments the compositions of the invention may also comprise multrlayered forms containing a combination of fast dissolve and slow dissolve layers. As used herein the term multilayered is not limited to discrete layers of materials but can also include mixtures of particles having slow dissolve and fast dissolve properties.

In certain embodiments of the invention, the composition is formulated to allow for immediate systemic absorption of phenylephrine. In additional embodiments of the invention, the composition is formulated to allow for sustained systemic absorption of phenylephrine. In additional embodiments of the invention the composition is formulated to allow for both an immediate systemic absorption and a sustained systemic absorption of phenylephrine.

In certain embodiments the composition is suitable for sublingual administration such that the composition allows for systemic absorption of phenylephrine from the floor of the mouth. In certain embodiments the composition is suitable for buccal administration such that the composition allows for absorption of phenylephrine from the buccal mucosa. Buccal mucosa has excellent accessibility with the direct access to the systemic circulation through the internal jugular vein which would bypass phenylephrine from the presystemic metabolism. Certain embodiments of the invention suitable for buccal administration can include matrix tablets and films. In certain embodiments the compositions of the invention suitable for buccal administration will have at least one of the folϊowings properties: (i) adhere to the buccal mucosa for few minutes to several hours; (ϊi) release phenylephrine by either or both of immediate burst or controlled release; (iii) release phenylephrine in an unidirectional manner directly to the mucosa or all directions; (iv) facilitate drug absorption through buccal mucosa; (vi) adapted to not interfere with normal function such as talking or drinking.

In certain embodiments the composition of the invention can comprise a dissolvable composition comprising phenylephrine distributed within an aqueous soluble base material, wherein the composition is provided as a strip for inter-oral administration of phenylephrine to the mucus membranes of the mouth of a human or animal subject. In certain embodiments, the dissolvable composition can comprise a base material comprising a carrier which is conformed as a strip to serve as a delivery system for a measured dose of phenylephrine. In certain embodiments, the strip can be a film impregnated with, coated with or otherwise carry phenylephrine to enable the distribution of the phenylephrine to the oral cavity. The films generally comprise one or more water-soluble or water-swellable thermoplastic polymers such as hydroxypropylceilulose, polyethylene oxide, homopoiymers and copolymers of carboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose) with or without a plasticizer. The strip/film can have a thickness suitable for oral administration to a subject, typically of from about 20 microns to about 250 microns,

In certain embodiments, the composition may comprise part or all of the phenylephrine or pharmaceutically acceptable salt thereof encapsulated within encapsulation structures. The encapsulation structures may be selected to provide adhesion to the mucous membranes of the oral cavity and/or be adapted to release the phenylephrine slowly over time. In certain embodiments, the encapsulation structures may comprise multilamellar microparticles.

In certain embodiments, the composition of the invention can comprise a bioerodible, water-soluble, carrier device comprising a non-bioadhesive backing layer, a bioadhesive layer and a composition comprising phenylephrine or a pharmaceutically acceptable salt thereof. In certain embodiments, the bioadhesive layer may be formulated to adhere to an oraϊ mucosa! surface to enable sustained delivery of the composition. In certain embodiments the carrier device may further comprise a fluid carrier suitable for administration to a mucosal surface of a mammal. The fluid carrier may comprise one or more of such materials as acetic acid, acetone, anisole, 1-butanof, 2-butanol, butyl acetate, tert- butylmethyi ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, methanol, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-i-butanol, methyfethyl ketone, methyiisobutyl ketone, 2- methyl-1 -propanol. pentane, 1 -pentanol, 1-propanol, 2-propanoi, propyl acetate, or tetrahydrofuran. In certain embodiments, the carrier device may further comprises a polymeric or nonpolymeric hydrophilic agent, such as polyethylene glycol.

In certain embodiments, the compositions of the invention can comprise a non-bioadhesive backing layer such as a pharmaceutically acceptable, film- forming, water-sofuble polymer. Examples of pharmaceutically acceptable, film- forming, water-solubie polymer include, but are not limited to, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyimethyl cellulose, hydroxyethylmethyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, ethylene oxide-propylene oxide co-polymers, and combinations thereof.

In certain embodiments, the composition of the invention may comprise a distribution of multilayer microparticles in a base, wherein phenylephrine or a pharmaceutically acceptable salt thereof is adsorbed within the layers of the microparticles so as to be progressively released over time to the buccal or sublingual mucosa. Compositions containing such microparticles can be administered by various means, such as film, gel, capsule, tablet, aerosolized or otherwise pressurized spray, non-pressurized pump spray, mousse or drench, etc. In certain embodiments, the distribution of multilayer microparticles is in the form of a soluble solid or ge! base, the base material being formulated to dissolve within the mouth and liberate the microparticles to allow for contact of the microparticles with the mucous membranes of the oral cavity. In certain embodiments, multilayer microparticles are in the range 0.1-10 microns. In certain embodiments, the microparticies may comprise polar structures with a positive surface charge Io allow for adhesion to mucosa! surfaces, U.S. Patent Hc. 6,861 _s066 describes the use of high shear rates, such as with a microfϊuidizer, to produce uniform submicron particle and droplet sizes of chemical or particulate substances.

In certain embodiments, the compositions of the invention may provide for a sustained release of phenylephrine to provide a measurable biood levels of parent (unmetabolized) phenylephrine in a subject for a sustained period of tϊme,wherein the period of time is at least about 5, 10, 15, 30, or 45 minutes, or at least about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, or 24 hours.

In certain embodiments, the compositions of the invention may contain additional therapeutic agents in addition to phenylephrine. The additional therapeutic agent may be a decongestant including anti-histamine, an anti-pyretic, a non-steroidal anti-inflammatory, or any other therapeutic agent or combination of two or more of such agents to assist alleviation of the symptoms of a cold, a seasonal or non-seasonal allergy, hay fever, or sinus problems. In a preferred embodiment, the pharmaceutical compositions include an antihistamine.

Antihistamines can be of H 1 or H2 antagonists or other types of histamine release inhibitors. The H1 antagonists can be sedating or non-sedating, such as diphenhydramine, chlorpheniramine, trϊpeiennamine, promethazine, clemastine, doxylamine, astemizole, terfenadine, and loratadine, among others. Examples of H2 antagonists include, but are not limited to, cimetidine, famotidine, nizatidine, and ranitidine. Examples of histamine-release inhibitors include cromolyn. Long- acting antihistamines selected from one or more of the group consisting of loratadine, desloratadine, azatidine, fexofenadine, terfenadine, cetirizine, astemizole, and Sevocabastine, or their pharmaceutically acceptable salts are suitable for the pharmaceutical compositions of the invention.

Preferred antihistamines include loratadine and desloratadine. Loratadine is disclosed in U.S. Patent No. 4,282,233 as a non-sedating antihistamine useful, for example, in alleviation of seasonal allergic rhinitis symptoms such as sneezing and itching. The active metabolite of loratadine is desloratadine, which has a half- life (t_t/₂} of approximately 15 to 19 hours, U.S. Patent No. 5,595,997 discloses methods and compositions for treating seasonal allergic rhinitis symptoms using desloratadine, Loratadine and desloratadine are available in the form of conventional tablets that release the active agent in a conventional manner. An exemplary formulation releases loratadine by the processes of disintegration and dissolution such that loratadine begins to elicit its antihistaminic effect within 1 to 3 hours and the effect lasts in excess of 24 hours. Due to the long half life of toratadine compared to phenylephrine, the loratadine in the formulation according to the present invention is preferably available for immediate release. For example, ioratadine or desloratadine may be present in solution in the carrier liquid of a liquid core or incorporated into the top coating of the product. Other antihistamines are also useful for the practice of the instant invention. Azatadine is disclosed in Belgian Patent No. 647,043 and in corresponding U.S.

Patent No. 3,326,924 and 3,419,565. The elimination half-life is reported to be 9- 12 hours. Terfenadine and fexofenadine are disclosed in U.S. Patent No. 3,878,217 and have a duration of action of 12 to 24 hours, and greater than 24 hours, respectively. Cetirizine is disclosed in U.S. Patent No. 4,525,358 and is reported to have a duration of action of 12 to 24 hours. Astemizole is disclosed in

U.S. Patent No. 4,219,559 and is reported to have a duration of action greater than 24 hours. Levocabastine is disclosed in U.S. Patent No. 4,369,184 and is reported to have a duration of action of 16 to 24 hours. The dosage of antihistamine such as loratadine or desloratadine may be present in different concentrations such as 1 - 20 mg; preferably 2.5 mg, 5 mg, or 10 mg.

Suitable anti-inflammatory and/or antipyretic agents useful for the present compositions may be: a non-steroidal anti-inflammatory (NSAIDs), aminoarylcarboxylic acid derivatives such as enfenamic acid, etofenamate, flufenamic acid, isonixin, meciofenamic acid, mefanamic acid, niflumic acid, talnifiurnate, terofenamate and tolfenamic acid; arylacetic acid derivatives such as acemetacin, aiclofenac, amfenac, bufexamac, cϊnmetacin, clopirac, diclofenac sodium, etodoϊac, fefbinac_; fenciofenac, fenctorac, fenctozic acid, fenfϊazac, glucametacin, ibufenac, indomethacϊn, isofezolac, isoxepac, lonazolac, metiazinic acid, oxametacine, proglumetacin, suϋndac, tiaramide, tolmetin and zomepirac; aryibutyric acid derivatives such as bumadizon, butibufen, fenbufen and xenbuctn; arylcarboxylic acids such as cϋdanac, ketorolac and tinoridsne; arylpropionsc acid derivatives such as afrnlnoprøfen, benoxaprofen, buctoxϊc acid; carprofen, fenoprofen, fluooxaprofen, flurbiprofen ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, miroprofβn, naproxen, oxaprozin, piketoprofen, pirprofen, pranoprofen, protizinic acid, suprofen and tiaprofenic acid; pyrazoles such as difenamizoie and epirizole; pyrazolones such as apazσne, benzpiperyfon, fβprazone, mofebutazone, morazone, oxyphenbutazone, phenybutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone and thiazolinobutazone; salicylic acid derivatives such as acetaminosaloi, aspirin, benoryiate, bromosaligenin, calcium acetylsalicylate, diflunrsal, etersalate, fendosaj, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetyisalicyiate, mesalamine, morpholine salicylate, 1 -naphthyl salicylate, olsaiazine, parsalmtde, phenyl acetySsaiicylate, phenyl salicylate, salacetamide, salicyiamϊne o-acetic acid, saltcylsulfuric acid, salsalate and sulfasalazine; thiazinecarboxamides such as droxicam, isoxicam, piroxicam and tenoxicam; others such as y-acetamidocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole and tenidap; and pharmaceutically acceptable salts thereof; and other analgesics, such as acetaminophen. The dosage of analgesic and/or antipyretic such as aspirin, acetaminophen, etc. will be known to those skilled in the art and can be in the range of 80 mg to 250 mg. The dosage of NSAID will be known to those skilled in the art and can be in the range of 80 mg to 500 mg.

Certain embodiments of the compositions of the invention are designed to release phenylephrine unidirectionally targeting the oral mucosa. Additional embodiments of the compositions of the invention are designed to release phenylephrine multidirectionally directly to the mucosa and into the saliva. Certain embodiments of the compositions of the invention may also contain a pharmaceutically acceptable bioadhesive or mucoadhesive additive to promote retention of the composition in the oral cavity for a period of time to allow for sustained release of phenylephrine. Examples of pharmaceutically acceptable bioadhesϊves and rnucoadhessves are known in the art and include, but are not limited to, cellulose derivatives such as hydroxypropyl cellutose, and others as described in U.S. Patent No. 4,940,587. In certain embodiments, the bioadhesive layer can be water-soluble or non-water soluble. Certain water soluble bioadhestve layers include film forming water-soluble polymers and bioadhesive polymers. Examples of film forming water soluble polymers include, but are not limited to, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyi cellulose, hydroxyethylmethyl cellulose, and combinations thereof. In certain embodiments, the film forming water soluble polymer of the bioadhesive layer is crosslinked or plasticized. Examples of bioadhesive polymers include, but are not limited to, polyacrylic acid, sodium carboxymethy! cellulose or polyvinylpyrrolidone and combinations thereof. In certain embodiments, potyacrylic acid can be fully or partially crosslinked. Examples of mucoadhesives include gels, pastes, macromoiecules, polymers, and oligomers, and mixtures thereof that can adhere to a subject's mucous membrane for a period of time sufficient to deliver the active agent such as described in U.S. Patent No, 6,509,028. in certain embodiments the compositions of the invention comprise at ieast one or a combination of biodegradable polymers to form a matrix with the phenylephrine or pharmaceutically acceptable salt thereof such that the matrix would provide an instant phenylephrine release upon contact with oral mucous without taking any water. In certain embodiments, the matrix can be in the form of a film or lattice comprising the biodegradable polymers. Such polymers are known in the art and can be selected from non-limiting examples including gelatin, dextran, dextrin, alginates (i.e., sodium alginate), hydroxypropyl methylcefluϊose (HPMC), hydroxypropylcellulose, carboxymethylceliulose or its salt, polyvinyl alcohol, polyvinylpyrrolϊdine, sucrose or other compressible sugars, dextrose, dextrate, maltodextrine, starch, modified starch, micrσcrystalline cellulose, siiidified microcrystalline cellulose, polyethylene glycols, lactose or with other pharmaceuticafly acceptable carrier materials. In certain embodiments, the compositions of the invention may also contain a pharmaceutical wax could be added for better performance.

The compositions of the invention may optionally comprise a penetration enhancer. Examples of penetration enhancers are: salicylates such as sodium salicylate, 3-mefhoχysaficytete, 5-mβthoxysaϋcyiate and homovanilate: bite acids such as taurochollc tauonodeoxychoiic, deoxychoiic, chølic, giychoϋc, lithocholate. chenodeoxycholic, ursodeoxycholic, ursocholfc_s dehydrochofic, fusϊdϊc, etc.; noπ- tonic surfactants such as polyoxyethylene ethers (e.g. Brij 36T⁸, Brij 52^Φ, Brij 56^®, Brij 76^®, Brij 96^®, Texaphor^® A6, Texaphor^® A 14, Texaphor^® A60 etc.), p-t-octy! phenol polyαxyethytenes (Triton^® X-45, Triton^® X-100, Triton^® X-114, Triton^® X- 305 etc.) nonyfphenoxypoioxyethylenes (e.g. fgβpaP CO series), poSyoxyethytene sorbitan esters (e.g. Tween^®-20, Tweβn^®-80 etc.); anionic surfactants such as dioctyt sodium sulfosuccinate; lyso-phospholipids such as lysolecithin and lysophosphatidylethanolamine; acylcarnitines, acylcholines and acyi amino acids such as lauroylcamitine. myristoyfcarnitine, palmitoylcarnitine, lauroylcholine, myristoylchoiine, palmitoylcholine, hexadecyllysine, N-acylphenylalanine, N- acylgiycine etc.; water soluble phospholipids; medium-chain glycerides which are mixtures of mono-, di- and triglycerides comprising medium-chain-length fatty acids (caprylic, capric and iauric acids); ethylene-diaminetetraacetic acid (EDTA); cationic surfactants such as cetyfpyridinium chloride; fatty acid derivatives of polyethylene glycol such as Labrasol^®, Labrafac^®, etc.; and alkylsaccharides such as lauryl maltoside, lauroyl sucrose, myristoyi sucrose, and palmitoy! sucrose.

Certain embodiments of the compositions of the invention may comprise one or more solubilizing agents with phenylephrine or other active agents to promote rapid dissolution in aqueous media. Suitable solubilizing agents include wetting agents such as polysorbates and poloxamers, non-ionic and ionic surfactants, food acids and bases (e.g. sodium bicarbonate), and alcohols, and buffer salts for pH control. Suitable acids include, but are not limited to, acetic acid, ascorbic acid, citric acid, and hydrochioric acid.

Certain embodiments of the compositions of the invention may comprise buffering materials to assist in absorption of pharmaceutically active ingredients. Certain embodiments of buffered formulations may include sodium carbonate, sodium phosphate, calcium carbonate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, or combinations thereof and other similar substances known to those skilled in the art. Certain embodiments of the invention wili optionally contain taste masking agents, such as flavors and/or sweeteners. The compositions may further comprise one or more lubricating and/or moisturising oils, including but not limited to hyaluronic acid or sodium hyaluronate, glycerol, catenduia officinalis ftower extract or glycerin extract, guar hydroxypropyttrimonium chloride, xanthan gum, cellulose gum, sodium chloride, olive oil, sunflower oil, almond oH, sesame oil, aioe vera, aloe barbadensis, and combinations thereof.

General process for manufacturing the formulations

Another aspect of the invention are the processes of manufacturing the formulations described above. The solid formuiations are prepared using methods generally known in the art to prepare orally delivered, single layer and multiple-layered dosage forms. See, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. {1975), and

Liberman, H. A, and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y. (1980). Stability and degradation analyses can be performed according to the international Conference on Harmonization (ICH) standards as described in Impurities in New Drug Products" guidelines to simulate two or more years of shelf life. For example, stability testing can be performed at 40 degrees Celsius / 75% relative humidity for a 3-month period. Standard pharmaceutical storage conditions are known in the art. Compositions according to the invention can be assayed to meet all ICH guidelines for active pharmaceutical assay with degradant levels which are below reporting limits, preferably below identification limits, and most preferably below qualification limits.

The compositions of the invention can be packaged maintain stability of the product. Preferred packaging methods include strip lamination in a foil-like material or packaging in blisters using a foil or teflon-like material.

Methods of treatment and administration

The methods of the invention are directed to administration of the pharmaceutical compositions for temporary relief of congestion and/or stuffiness caused by colds, seasonal and other allergies, hay fever, sinus problems or allergic and non-allergic rhinitis, which may cause an increase in nasal discharge. In certain embodiments the composition of the invention provides a therapeutically effective phenylephrine dose for at period of time after a single dose is administered to a subject. The subject can be any animal, human or otherwise, in need of treatment with phenylephrine. The period of time contemplated can be anywhere from 5 minutes to over 24 hours. It is contemplated that, by bypassing the first pass metabolism of the subject, a sustained therapeutic dosage can be obtained for a period of time from a single administration of the compositions of the invention that would be therapeutically equivalent to oraliy administered immediate release compositions that are typically administered in multiple dosages and absorbed through the gastrointestinal tract. Thus, when viewed in terms of pharmacokinetic parameters, a single administration of certain embodiments of the compositions of the invention will provide phenylephrine to the subject such that the subject exhibits a mean AUC and/or C_maχ of phenylephrine equivalent to from about 80% to about 125% of the

AUC and/or C_maχ obtained by multiple doses of a standard immediate release oral dosage formulation of phenylephrine. Such standard immediate release oral dosage formulation of phenylephrine typically contain about 10mg of phenylephrine and are administered in multiple doses, such as 2, 3, 4, 5, 6, or more doses, over a 24 hour period to provide for sustained therapeutic dosages.

Thus, certain embodiments of this invention provide a therapeutically effective phenylephrine dose for a period of time after a single dose is administered to a subject, wherein the period of time is at least about 5, 10, 15, 30, or 45 minutes, or at least about 1 , 2, 3, 4, 5, 6, 7, 8, 9_t 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23_» or 24 hours. In addition, certain embodiments of the invention are formulated as a single dosage form to deliver phenylephrine or a pharmaceutically acceptable salt thereof to a subject in need thereof, such that the single dosage results in peak concentration of unmetabolized phenylephrine in plasma of the subject at a time point of from about 0.1 and about 1.5 hours after the composition contacts the oral mucosa. In certain embodiments of the invention, the amount of unmetabofized phenylephrine m the subject is maintained at a level greater than 20 picogram/mf. in certain embodiments of the invention, the amount of unmetabolized phenylephrine in the subject is maintained for a period of about one half to 12 hours after placing the composition in contact with the oral mucosa. The presence of unmetabolized phenylephrine is detectable by methods used by one skilled in the art for detecting pharmaceutical compounds in the plasma (P. Ptacek, et al. J. Chromatography B, 858 (2G07),263 - 288). As used herein, the term "contacting of the oraϊ mucosa" can comprise placing the composition of the invention under the tongue or on the floor of the mouth or in contact with the buccal mucosa. In certain embodiments of the invention, the compositions wii! contact the oral mucosa by means of placing a solid, semi-solid, or liquid form of the composition in the mouth. These methods of contacting may also include spraying the composition into the mouth in a manner that the composition is applied to the oral mucosa.

Thus, the invention further provides a method of systemicaliy administering phenylephrine to a subject which comprises contacting oral mucosa with a pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable sail thereof, wherein the composition allows for absorption of phenylephrine by oral mucosa. In certain embodiments, the invention includes methods of treating symptoms of cold, influenza, or allergies in a subject in need thereof, comprising administering the pharmaceutical compositions described herein. In certain embodiments, the methods comprise administering the pharmaceutical composition every 8, 12, 16, or 24 hours.

In certain embodiments, the method of the invention comprises administering phenylephrine to the floor of the mouth underneath the tongue of the subject, In certain embodiments, the method of the invention comprises administering phenylephrine to the buccal mucosa of the subject.

Phenylephrine Metabolite Activity Assays

The affinity and activity of phenylephrine metabolites were evaluated in human recombinant cti and α₂ adrenoreceptor binding and activity assays. PE undergoes extensive pre-systemϊc metabolism. After oral administration of approximately 24 mg of PE to healthy volunteers, four main metabolites were excreted in the urine (10). These metabolites are: 1 ) unconjugated m- hydroxymandeiϊc acid (30% of dose); 2) sulfate conjugate of m~ hydroxyphenyfglycol; 3) sulfate conjugate of PE (47%); and 4) glucuronide conjugate of PE (12%). The purpose of the present studies was to determine the affinity and functional activity of m-hydroxymandelic acid, PE sulfate conjugate and PE glucuronide conjugate at the human recombinant α_radrenoreceρtors {α_1a and Ot_Ii₃ subtypes) and α₂-adrenoreceptors (α_2a. α_2b and a_2c subtypes). Affinity of the metabolites was determined by receptor binding assays. Functional activity of the metabolites was assessed using an [³⁵S]-GTPγS binding exchange assay for the α₂ receptor subtypes and a cell-based calcium flux response for the oti receptor subtypes.

The major metabolites of PE were evaluated to determine their ability to bind to or activate the Ot₁ adrenoreceptor subtypes α_1a and α_1b and the α₂ adrenoreceptor subtypes α_2a, α_Ξb and α_2c- The metabolites evaluated were: 3- hydroxymandelic acid, PE sulfate and PE glucuronide. in each binding and functional assay the metabolites were compared to PE.

Materials And Methods

(RH-)-phenyleρhrϊne (PE), was obtained from Sigma {Cat. no.P6126-25G, CAS [61 -76-7]). 3-hydroxymande!ic acid, also known as m- hydroxymandelic acid, was obtained from Fluka (Cat no.55520-1G, CAS [17119-15-2]), and characterized as described (11). (R)-PE sulfate was prepared as described from PE (11 ). By NMR (R)-PE-suIfate batch 4 was estimated to contain less than 0.1 %

PE (11). (R)-PE glucuronide was prepared as described (11 ). Two batches were prepared : batch 2 ("b2") or batch 4 (^<fb4^H). The amount of PE in the PE- glucuronide was estimated to be undetectable (b2) or ~ 0,28 % (b4) by LC/MS

(1 1 ).

[³⁵S]-GTPTS binding

Membranes (20 μg/well) from Chinese hamster ovary (CHO) cells expressing each of the α₂ adrenoceptors were incubated for 30 minutes at room temperature with seriat dilutions of phenylephrine (PE), PE metabolites or the standard, UK14304, or 1 μM cold GTPγS (non-specific binding) and 0.1 nM [³⁶S]-

GTPγS in quadruplicate In NEN Basic RashPiates^®. Assay buffer was 75 mM Tris-HCl pH 7.4, 12.5 mM MgCf₂, 2 mM EDTA and 1 μM GDP, Plates were counted on a Packard TopCount. The percent increase over basal binding of [³⁵S]-GTPyS , a measure of efficacy, was calculated as follows : 100 x [(mean total sample cprn ~ basai cpml ÷ by basal cpm]. Basai cpm was defined as the mean cprn in the absence of agonist compound minus the mean non-specific binding cpm. Half-maximal effective concentrations (EC₅₀, concentration of compound required to give 50% of its own maximal stimulation) were calculated using nonlinear regression with GrapbPad Prism.

Competition binding assays

5 Competition binding assays for the α₂ adrenoreceptors were performed using 20 μg membrane protein per well in binding buffer (75 mM Tris-HCI pH 7.4, 12.5 mM MgCi₂, 2 mM EDTA, 0.2% bovine serum albumin). [³H]-UKI 4304 was used as the radioligand. Competition binding for the αi adrenoreceptors was performed similarly with [³H]-Prazosin as the radioligand. The K_d of [³H]-UKI 43040 for α_2a , ci_2b and α₂c is ; 0,9, 26.5 and 2.4 nM, respectively. The Kd of [³H]-Prazosin for α-i_a and α-ι_b is 0.2 and 0.3 nM, respectively. Competition binding was done using various concentrations of PE or PE metabolites as the cold competitor. Binding was terminated by rapid filtration through GF/C unifiiter plates, presoaked with 0.3% polyethylenimine, with five washes with 0.5 ml cold 50 mM Tris-HCI ph5 7.4, using a Packard Filtermate Harvester. After drying, bound radioactivity was determined by liquid scintillation counting (Packard TopCount) with Microscint 20, 50 μl/well. Binding data were analyzed using GraphPad Prism.

Cellular Calcium flux 0 Intracellular calcium levels were measured using a fluorometric imaging plate reader (FLIPR). Cells expressing αi adrenoreceptors were cultured overnight at 15,000 celis/weli in 96 well black-wall clear bottom plates (Packard). Adherent cells were loaded for 1 hour at 37° C using the FLIPR Calcium Plus Assay Kit (Molecular Probes, Eugene, OR), which included 2.5 mM probenecid 5 (Sigma), Compounds (at 10 mM in 100 % DIvISO) were diluted in diluting buffer

(HBSS, 20 mM HEPES, 2.5 mM probenecid, 0.5% BSA, pH 7.4). A titration of norepinephrine was included in every experiment and norepinephrine (at 1 μ!V1) was also used as a plate standard on each assay plate. Cells were maintained at 37° C throughout all calcium measurements. Fluorescence data was collected at 1 C second interval for 60 seconds, followed by collection at 2 second intervals for 30 seconds. Background fluorescence was quantifafed in welte containing ceils with no additions and was subtracted from all experimental samples, AH conditions were done in quadruplicate. Non-linear regression analysis using GraphPad Prism was used to calculate EC₅₀ values.

Data Analysts

PE was tested as a reference compound in all assays. Each metabolite was evaluated in each assay in at least 2 independent experiments and a representative assay of each metabolite/assay combination is shown. EC₅₀ and K₁ values are expressed as mean ± SD of 2-4 independent assays .

A fow level of PE was estimated to be present in the PE sulfate (less than

10 0.1%) or in PE giucuronide batch 4 (approximately 0.28%). Theoretical dose response curves were generated using nonlinear regression (Graphpad Prism) to estimate the activity expected if PE were present in the PE sulfate at 0.1% or in PE giucuronide batch 4 at 0.28%.

15 Results

The potency and affinity of PE and all PE metabolites tested are summarized in Table 1.

TABLE 1

3-

PE hydroxymandelic

PE PE sulfate giucuronide acid

Receptor Assay EC50 κ» EC₅₀ K₁ EC₅₀ K₁ EC₅₀ a1a Calcium 101 NA M NA al b Calcium 14 NA M NA a1a Binding 1873 NA NA NA alb Binding 6737 NA NA NA a2a GTP7S 225 NA NA NA a2b GTPγS 2334 NA NA NA a2c GTPyS 884 NA NA NA a2a Binding 130 NA M NA a2b Binding 558 NA M NA a2c Binding 67 NA M NA

?.S, Numerical values represent mean Ki or EC₅₀ nM

NA = Not Active

M = Not Active or Minimal activity in b4 consistent with PE contamination PE induced an increase in intracellular calcium in cti_a- (EC₅₀ = 101 ± 52 nM) and α_1tj-expressing CHO cells (EC₅₀ = 13.6 ± 20.6 nM), In contrast, 3- hydroxymandeiic acid was not active in the α_1a and oci_b calcium assays (Figure 1 ). PE demonstrated binding to the ot_1a (K; = 1873 ± 1043 nM) and αi_b receptors (K, - 6737 + 5650 nM). No appreciable binding to these receptors was detectable with 3-hydroxymandeSic acid at concentrations up to 100 μM (Figure 2).

In an [³⁵S]-GTPγS binding exchange assay, PE demonstrated functiona! activity for the α≥ receptor subtypes. The potency of PE for the α_2a, cc₂b and α_2c subtypes is 225 ± 46 nM, 2334 ± 522 nM, and 884 ± 312 nM, respectively, in contrast, 3-hydroxymandeIic actd had no activity in the α_2ai ct2b and α_2c ^Ϊ353S-

GTPγS assays (Figure 3). Also, 3-hydroxymandelic acid demonstrated no significant binding to the oc₂ receptor subtypes (Figure 4). In contrast, PE bound to the α_Ξa, «2_b and α_2c receptors with moderate affinity : Ki = 130 ± 15 nM, 558 ± 188 nM, and 67 + 16 nM, respectively, In contrast to PE, PE sulfate had no or minimal activity in the Oι_a or αi_b calcium assays, respectively (Figure 5). Theoretical curves were also generated to indicate the activity expected if PE were present in PE sulfate at 0,1 %, the limit of detection of PE by NMR. in both assays the activity of PE sulfate was much less than expected for PE if PE were present at the limit of assay detection (Figure 5). No appreciable binding of PE sulfate was detected at the α_1a and α-ib receptors

(Figure 6).

PE sulfate was also assessed for activity at the a_2a, α_2b and α_2c subtypes using the [³⁵S]-GTPγS assays (Figure 7). No activity of PE sulfate was detected and this was less than that expected for PE if PE were present at the limit of assay detection, in addition, no appreciable binding of PE sulfate was observed at the α₂ receptor subtypes (Figure 8). The very minimal binding detected at 100 μM at each receptor subtype was fess than that expected for PE if PE were present at the limit of assay detection,

PE giucuronide was evaluated in the assays described above, PE glucuronide b4 was estimated to contain approximately 0.28% PE and was evaluated tn the oci calcium assays (Figure 9) and α_£ binding assays (Figure 12). PE giucuronide b4 was - 300-450-fold tess potent than PE in inducing a calcium increase in the α_1a or α_1b ceifs (Figure 9). Theoretical curves were also generated to reflect the activity expected for contaminating PE which was present in PE glucuronic^ at approximately 0.28%. in both assays the activity of PE glucuronide was similar to or slightly less than that expected for PE if PE were present at 0.28% (Figure 9).This indicates that the weak activity of PE glucuronide is attributable to the low level of contaminating PE,

PE glucuronide b2, with no detectable PE, was evaluated in the oti binding assays (Figure 10). No appreciable binding of PE glucuronide was detected at the ecu and α-ι_b receptors (Figure 10). In the α₂ [³⁵S]-GTPyS assays (Figure 11 ), PE glucuronide b2 stimulated very weak binding to α_2a membranes only at the highest concentration tested, 100 μM. No stimulatory activity was observed in α₂b and α_2c membranes.

A small amount of binding of PE glucuronide b4 was observed at the α₂ receptor subtypes which was significantly less than that of PE (Figure 12} and Ki values could not be determined. Theoretical curves were generated to reflect the activity expected for contaminating PE which was present in PE glucuronide b4 at approximately 0,28%. in all α₂ receptor binding assays the activity of PE glucuronide b4 was simitar to that expected for PE if PE were present at 0.28% (Figure 12).This indicates that the weak activity of PE glucuronide is attributable to the Sow level of contaminating PE.

Conclusions

3-Hydroxymandelic acid had no activity at the highest concentration evaluated (10 μM) in the αi or α₂ assays assessing agonist activity. Both the calcium fiux assay and the [³⁵S]-GTPyS binding exchange assay are considered sensitive assays of m and a_∑ adrenoreceptor activity, respectively, because each utilizes celts overexpressing the recombinant human adrenoreceptors. In addition, 3-hydroxymandelic acid had no affinity for the αi or α₂ receptor subtypes at the highest concentration evaluated (100 μM). Thus, 3-hydroxymandelic acid is an inactive metabolite of PE,

PE sulfate had no affinity for the «i or α₂ receptor subtypes at the highest concentration evaluated (100 μM). PE sulfate had no activity in the α₂ subytpe [³⁵S]-GTPγS assays at the highest concentration evaluated (100 μM). A very low level of activity was detected in the α_t calcium assays and this activity was much less than expected for PE if PE were present at the limit of assay detection. Thus, PE sulfate has minimal to no activity at the αi or α₂ adrenoreceptors. PE glucuronide was pharmacologically inactive in the αi and a₂ subtype receptor binding assays as welf as in the assays measuring functional activity of the αi and az receptors. PE glucuronide had no binding affinity for the oci_a or α_ib receptors nor did it activate binding of [³⁵S]-GTPyS to the a₂ receptor subtypes. The minimal activity of PE glucuronide batch 4 observed in the oti_a and α-i_b calcium and α₂ receptor binding assays was completely consistent with the level of contaminating PE (0.28%).

REFERENCES

1. Johannssen, V., S, Maune, JA Werner, H. Rudert, and A. Ziegler. 1997.Alpha 1-receptoπ at pre-capitlary resistance vessels of the human nasal mucosa. Rhinoiogy 35 : 161-165.

5 2, Rizzo, C. A., L. M. Ruck, M. R. Corboz, S. P. Umland, Y. Wan, H. Shah, J. Jakway, L

Chen, K. McCormick, R. W. Egan, J. A, Hey. 2001. Postjunctional ₂c-adrenocepto contractility in human saphenous vein. Eur. J. Pharmacol. 413 : 263-269.

3. Corboz, M. R., L. M. Varty, C. A. Rizzo, J, C. Mutter, M, A. Rivβlli, Y. Wan, S. Umland, H0 Giu, J. Jakway, K. D. McCormick, M. Beriin, and J. A. Hey. 2003. PharmacoSogica characterization of α₂-adrenoceptor-meidated responses in pig nasal mucosa. Autonomic and Autocoid Pharmacol. 23 : 208-219.

4. Johnson, DA, and J. G. Hricik 1993, The pharmacology of alpha-adrenergic5 decongestants. 1993. Pharmacotherapy. 13: 110S-115S.

5. Watase, T. and M. Okuda, 1986. The effects of autonomotroptc drugs on allergic nasa mucosa. Rhinoiogy 24: 181-186. Q 6. McLeod, R-, C. H. Erickson, G. G. Mingo, and J, A. Hey. 2001. Intranasal application oi the α≥-adrenoceptor agonist BHT-920 produces decongestion in the cat. Am. J. Rhinol. 15: 407-415.

7. Chua, S. S., and S. ). Benrimoj. 1988. Non-prescription sympathomimetic agents and5 hypertension. Med. Toxicol. Adverse Drug Exp. 3: 387-417.

8. Ramey, j. T., E. Bailen, and R. F. Lockey. 2006. Rhinitis medicamentosa. J. Investig Aliergol Clin Immunol. 16: 148-155. 0 9. Graf, P. 2005. Rhinitis medicamentosa : a review of causes and treatment. Respir. Med.

4- 21 -29.

10. Bruce, R. B,. and J, E, Pitts 1968, The determination and excretion of phenylephrine in urine. Biochemical Pharmacology 17, 335-337.

11. R. Aslanian, C. Boyce, V. Hegde, M, de Lera Ruiz, M. Senior, Y. Yu, L.K.Zhang. Synthesis and characterization of Phenylephrine metabolites. D-report #50144. July 9, 2007.

12. P. Ptacek, J. Klirna and J. Macek, Development an d validation of a liquid chromatography-tandem mass spectrometry method for the determination of phenylephrine in human plasma and its application to a pharmacokinetic study. J Chromatography B. 858 (2007) 236 - 268.

13. Aungst, B.J,, Rogers, N.J., and Shefter, E., Comparison of nasal, rectal, buccal, sublingual and intramuscular insulin efficacy and the effects of a bile salt absorption promoter, The J. Pharmacol. Exp. Ther., 244:23-27, 1988.

14. Yajaman S., Kuotsu K. and Bandyopadhyay A. K., Buccal bioadhesive drug delivery - A promising option for oarally less effective drugs, J. Controlled. Release. 1 14:2006, 15-40.

15. Rathbone, M.J. and Hadgraft, J., Absorption of drugs from the human oral cavity, Int. J. Pharm., 74:9-24, 1991.

16. Squier, C.A., The permeability of oral mucosa, CrIt. Rev. Oral Biol. Med., 2:13-32, 1991 . 15. Squier, C

17. Squier, CA, and Wertz, P W. Structure and function of the oral mucosa and implications for drug delivery, in eds. MJ. Rathbone. Oral Mucosa! Drug Delivery, Marcel Dekker, Inc., New York, New York, 1-26, 1996.

18. Galey, W. R., Lonsdale, H. K., and Nacht, S., The in vitro permeability of skin and buccal mucosa to selected drugs and tritiated water, J. Invest. Dermal, r,7V: S-717. 19. Sawicki W and Janicki S, Pharmacokinetics of verapamil and its metabolite norverapamif from a buccal drug formulation, Int. J. Pharm., 238(2002) 181-189

20. Janet AJ. Hoogstraate and Philip W. Wertz, Drug Delivery Via the Buccal Mucosa, PSiT: 1(7) 1998: 309-313

21. Buket T., Yilmaz C, Olgun G., Sirri K,, and Atilla H., Design and Evaluation of Sustain-release and Buccal adhesive propranolol Hydrochloride tablets, J. Controlled Release, 38(1996): 11 -20

22. Ehrnebo M, Boreus LO and Lόnroth U., Bioavailability and first-pass metabolism of oral pentazocine in man, Clin Pharmacol Ther, 1977 Dec;22(6):888-92.

23. Varsha A., and Mishra B., Design, Deveiopment, and Biopharmaceuticai

Properties of Buccoadhesive Compacts of Pentazocine, Drug, Dev. fnds. Pharm, 25(6)1999:701-709

24. Bruce, R.B. and Pitts, J,E. (1968) The Determination and excretion of phenylephrine in urine. Biochemcial Pharmacology 17, 335-337.

25. Bruce, R.B. and Pitts, J. E. (1968) The Determination and excretion of phenylephrine in urine. Biochemcial Pharmacology 17, 335-337.

26. Ibrahim, K.E. et al. (1983) The Mammalian Metabolism of R-(-)-m-

Synephrine. Journal of Pharmacy and Pharmacology 35, 144-147,

27. Gumbhir, K. (1993) An Investigation of Pharmacokinetics of Phenylephrine and its Metabolites in Humans. In Pharmaceutical Sciences, pp. 216, University of Missouri-Kansas City.

28. Hengstmaπn, J, H. and Goronzy, j. (1982) Pharmacokinetics of ³H-

Phenylephrine in Ivian. European Journal of Clinical Pharmacology 21 , 335-341 29. Stockis, A. et al, (1995) Relative Bioavailability of Carbinoxamine and Phenylephrine from a Retard Capsule after Single and Repeated Dose Adminstration in Healthy Subjects. Arzneim.-Forsch./Drug Res. 45 (9), 1009-1012.

30. FDA. (2004) Proposed Rule - Docket No. 1976N-0052N/CP18. Cold, Cough, Allergy, Broncodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use; Proposed Ammendment of Monograph for Over-the-Counter Nasal Decongestant Drug Products, Federal Register 69 (211 ), 63482-63488.

31. Antonio, L et al. (2003) Glucuronidation of catechols by human hepatic, gastric, and intestinal microsomal UDP-glucuronosyltransferases (UGT) and recombinant UGT1 A6, UGT1A9, and UGT2B7. Archives of Biochemistry and Biophysics 411 , 251 -261.

32. Chen, G. et al. (2003) Human gastrointestinal sulfotransferases: identification and distribution. Toxicology and Applied Pharmacology ! 87, 186-197.

33. Doherty, M.M. and Charman, W.N. (2002) The Mucosa of the Small Intestine. How Clinically Relevant as an Organ of Drug Metabolism? Clinical

Pharmacokinetics 41 (4), 235-253.

34. Gregory, P. A. et al. (2004) Regulation of UDP glucuronosyltransferases in the gastrointestinal tract. Toxicology and Applied Pharmacology 199, 354-363.

35. Teubner, W. et al. (2007) Identification and localization of soiubie sulfotransferases In the human gastrointestinal tract. Biochemical Journal 404, 207-215

36. Radominska-Pandya, A. et al. (1998) UDP-glucuronosyltransferases in human intestinal mucosa, Biochemica et Biophysics Acta 1394, 199-208.

37. Pang, K.S. (2003) Modeling of Intestinal Drug Absorption; Rofes of Transporters and Metabolic Enyzmes (For the Gillette Review Series). Drug Metabolism and Disposition 31 ( 12) , 1507-1519.

38. Ilett, K. F. et at. (1990) Metabolism of Drugs and Other Xenobiotics in the Gut Lumen and Wall. Pharmcology and Therapeutics 46, 67-93.

39. Marathe, P. H. et al. (1995) Absorption and Presystemic Metabolism of Nefazodone Administered at Different Regions in the Gastrointestinal Tract of Humans. Pharmaceutical Research 12 (11), 1716-1721.

40. Kollar, C. et al. (2007) Meta-Anaiysis of the Efficacy of a Single Dose of Phenylephrine 10 mg Compared with Placebo in Adults with Acute Nasal Congestion Due to the Common Coid. Clinical Therapeutics 29 (6), 1057-1070.

The following examples describe certain embodiments of the compositions and methods of the invention. The examples are not intended, and shouid not be interpreted, to limit the scope of the invention which is more fuliy defined in the claims which appear thereafter.

EXAMPLES

Example 1

Orally disintegrating tablet dosage forms

The foilowing table shows a representative formulation for compositions of the invention in the form of an orally disintegrating tablet.

Table 2

The dosage forms are prepared by charging phenylephrine HCI, Avicel PH101 , and Povidone to a granuiator and mixing. The mixture is then granulated with water and passed through a screen, such as an 8 mesh screen. The granules are then dried, such as by using a tray dryer, and the dried granules are passed through a suitably-sized screening miii. The granulation is then mixed with selected excipients and pressed into tablets.

Example 2

Soft gel capsule dosage forms

The following table shows a representative formulation for compositions of the invention in the form of soft gel capsules.

Table 3

The formulations are prepared by weighing PEG 400 and water and mixing welϊ with a mixer. Phenylephrine HCI is then charged and mixed until all phenylephrine dissolved. The composition is then filled into softgef capsules. Example 3

Buccal tablet dosage forms

The following table shows a representative formulation for compositions of the invention in the form of buccal adhesive tablets having a diameter of approximately 7 mm and hardness 6 - 8 kP (kilopascai).

Tabϊe 4

The tablets are prepared by directly compressing a tablet mix containing between about 1 to about 75 mg of phenylephrine or pharmaceutically acceptable salt and about 90 to about 400 mg of excipients such as Carbopol® 971 P as bioadhesive polymer, magnesium stearate as lubricant, corscarmellose sodium as supper disintegrate, granular sugar (e.g. dextrose, multidextrine, manitol etc.), sucralose as artificial sweetener and artificial flavors using a rotatory tablet press.

Example 4

Lozenge dosage forms

Lozenges are flavored dosage delivery systems for medication that are held in the mouth, wetted with saiiva and sucked until dissolution occurs. A lozenge that dissolves slower is more preferable to allow for most of the drug to be absorbed from the buccal cavity and iess swallowed and tost in the Gl tract. The following table shows a representative formulation for compositions of the invention in the form of lozenges having a diameter of approximately 20 mm and hardness of between about 12 and about 30 kP.

Table 5

The lozenges are prepared by direct compressing a tablet mix consisting of 5 - 75 mg of phenylephrine and 80 - 900 mg of suitable excipients such as magnesium stearate, mannitol, carbopol 971 P and xanthan gum using a rotatory tablet press.

Examples 5-8

Buccal/Sublingual Film Dosage Form

The following table shows representative formulations for compositions of the invention in the form of rapidly disintegrating/dissolving films for oral consumption with no mucoadhesion, Table 6

^* Calculated assuming complete evaporation of water from the films after drying. Enough water is used to enable efficient processing.

Ingredient ranges for one film dose according to this aspect of the invention can be as follows: Table 7

The films in Examples 5 and 6 are prepared as follows. The film-forming ingredients (e.g. pullulan, xanthan gum, locust bean gum, and carrageenan) other than Poiysorbate 80 and Atmos 300 are mixed and hydrated in hot purified water to form a gel and stored in a refrigerator overnight at a temperature of approximately 4^"C to form Preparation A, The sweetener and Phenylephrine Hydrochloride are dissolved in purified water to form Preparation B. Preparation B is added to Preparation A and mixed together to form Preparation C. The flavoring agents (e.g. cooling agent and menthol) are mixed to form Preparation D. The Poiysorbate 80 and Atmos 300 are added to Preparation D and mixed well to form Preparation E which is added to Preparation C and mixed well to form Preparation F. Preparation F is poured on a rnofd and cast to form a film of desired thickness at room temperature. The film is dried using warm air and cut into desired dimensions, packaged and stored. The films will have a very rapid dissolving time, on the order of about 10 seconds.

The following tabfe shows representative formulations for compositions of the invention in the form of disintegrating/dissolving films for oral consumption with mucoadhesive properties:

Calculated assuming complete evaporation of water and ethanol from the films after drying. Enough water and ethanol is used to enable efficient processing. A preservative, e.g. sodium benzoate, can be added as an anti-microbial agent.

ingredient ranges for one film dose according to this aspect of the invention can be as follows: Table 9

I Ingredient Theoretical % (w/w) j Phenylephrine HCi or 1 - 25 (1 to 20 mg) similar salt

Sorbitol 1 - 5

KoHicton 30 1 - 3

Glycerol 1 - 10

Propylene Glycol 1 - 10

Sodium Benzoate 0.1 - 1

Aspartame 1 - 5

Polysorbate 80 1 - 7

Brij 35 5 - 12

Propylene Glycol 1 - 10

Hydroxypropylmethyl 20 - 40 cellulose

The films in Examples 7 and 8 are prepared as follows. Sorbitol, Kollidon 30, glycerol, propylene glycol, polysorbate 80, Brij 35, peppermint flavor and aspartame are dissolved in a sufficient amount of water and ethanoi (e.g. 800 gram for an approximate batch size of 75 gram) at 60^°C while stirring. After all the ingredients are dissolved (clear solution is obtained), add hydroxypropylmethyl cellulose (HPMC) while stirring. After the HPMC is completely dissolved, the solution is cooled to room temperature and coated onto a suitable carrier web (e.g. non-siliconrzed, poiyethylene-coated kraft paper) using conventional coating and drying conditions. Coating gap and web speed have to be adjusted to achieve a dry film thickness between 20 and 50 micron. The resulting film is peeled off the carrier web and cut into pieces of a suitable shape and size. Example 9

Semi-solid (chewing gum) dosage forms

The following table shows a representative formulation for compositions of the invention in the form of a semi solid chewing gum composition:

Table 10

The chewing gum compositions are comprised of a water insoluble chewing gum base portion, a water soluble portion includes sweeteners and phenylephrine or its pharmaceutically acceptable salt, fillers that may be insoluble or partially soluble and flavors and colorants. Phenylephrine and alt soluble ingredients except filler are dissolved in a mixing vessel and granulated with the fillers. The granulation is dried in a suitable dryer and then milled with suitable particle size distributions. The milled granulation is then mixed with gum base in a suitable mixer. The mix is then compressed into chewing gum using suitable rol! compression equipment.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition is formulated to be applied to oral mucosa to allow for enhanced systemic absorption of therapeutically active form of phenylephrine.

2. The composition of claim 1 wherein the composition is formulated to allow for immediate systemic absorption of therapeutically active form of phenylephrine.

3. The composition of claim 1 wherein the composition is formuϊated to allow for sustained systemic absorption of therapeutically active form of phenylephrine.

4. A pharmaceutical composition suitable for sublingual systemic administration of phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition allows for systemic absorption of phenylephrine from the floor of the mouth.

5. The composition of claim 4 wherein the composition is formulated to provide an immediate release of phenylephrine.

6. The composition of claim 4 wherein the composition is formulated to provide a sustained release of phenylephrine.

7. A pharmaceutical composition suitable for buccal systemic administration of phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition allows for absorption of phenylephrine from the bucca! mucosa.

8. The composition of claim 7 wherein the composition is formulated to provide an immediate release of phenylephrine.

9. The composition of ciairn 7 wherein the composition is formulated to provide a sustained release of phenylephrine.

10. The composition of claim 1 wherein the composition provides a release of phenylephrine to provide a measurable plasma concentration of therapeutically active form of phenylephrine in the subject for a period of at least four hours.

1 1 . The composition of claim 1 wherein the composition provides a release of phenylephrine to provide a measurable plasma concentration of therapeutically active form of phenylephrine in the subject for a period of at least six hours.

12. The composition of claim 1 wherein the composition provides a release of phenylephrine to provide a measurable plasma concentration of therapeutically active form of phenylephrine in the subject for a period of at least eight hours.

13. The composition of claim 1 wherein the composition provides a release of phenylephrine to provide a measurable plasma concentration of therapeutically active form of phenylephrine in the subject for a period of at least twelve hours.

14. The composition of claim 1 wherein the composition provides a release of phenylephrine to provide a measurable plasma concentration of therapeutically active form of phenylephrine in the subject for a period of at least sixteen hours.

15. The composition of claim 1 wherein the composition provides a release of phenylephrine to provide a measurable plasma concentration of therapeutically active form of phenylephrine in the subject for a period of at least twenty hours.

16. The composition of claim 1 wherein the composition provides a release of phenylephrine to provide a measurable plasma concentration of therapeutically active form of phenylephrine in the subject for a period of at least twenty four hours.

17. A method of systemϊcaϋy administering phenylephrine which comprises contacting oral mucosa with a pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, wherein the composition allows for release of phenylephrine to ora! mucosa.

18. A dissolvable composition comprising phenylephrine distributed within an

5 aqueous soluble base material, wherein the composition is provided as a strip for inter-oral administration of phenylephrine to the mucus membranes of the mouth of a human or animal subject.

19. The composition of claim 18 wherein base material comprises a carrier which0 is conformed as a strip to serve as a delivery system for a measured dose of phenylephrine.

20. The composition of claim 18 wherein the strip comprises phenylephrine coated on the strip. 5

21. The composition of claim 18 wherein the strip comprises a flexible film having a thickness of from about 20 microns to about 250 microns.

22. The composition according to claim 18 wherein the carrier or base material of 0 the strip comprises a soluble gel material.

23. The composition according to claim 1 wherein a part or all of the phenylephrine or pharmaceutically acceptable salt thereof are encapsulated within encapsulation structures. 5

24. The composition according to claim 23 wherein the encapsulation structures are selected to adhere to the mucous membranes of the oral cavity.

25. The composition according to claim 1 wherein the encapsulation structures C are selected to release the phenylephrine or pharmaceutically acceptable salt thereof slowly over time.

26. The composition according to claim 23 wherein the encapsulation structures comprise multilamellar microparticles,

27. A bioerodibie, water-soluble, carrier device comprising a non-bioadhesive backing layer, a bioadhesive layer and a composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, wherein the bioadhesive layer is formulated to adhere to a mucosal surface of a mamma! and provides sustained delivery of the composition,

28. The carrier device of claim 27 wherein the composition further comprises a fluid carrier suitable for administration to a mucosal surface of a mammal

29. The carrier device of claim 28 wherein the fluid carrier comprises acetic acid, acetone, anisole, 1-butanoi, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, methanol, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate,

3-methy!-1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methy!-1 - propanol, pentane, 1 -pentanol, 1 -propanoI, 2-propanol, propyl acetate, or tetrahydrofuran.

30. The carrier device of claim 27 wherein the composition further comprises a polymeric or nonpolymeric hydrophilic agent.

31. The carrier device of claim 30 wherein the hydrophilic agent comprises polyethylene glycol.

32. The carrier device of claim 27 wherein the bioadhesive layer is water-soiuble.

33. The carrier device of claim 27 wherein the bioadhesive layer comprises a film forming water-soluble polymer.

34. The carrier device of claim 27 wherein the bioadhesive layer comprises a bioadhesive polymer.

35. The carrier device of claim 33 wherein the film forming water soluble polymer of the bioadhesive layer comprises hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylmethyl cellulose, or a combination thereof.

36. The carrier device of claim 33 wherein the film forming water soluble polymer of the bioadhesive layer is crosslinked or plasticized.

37. The carrier device of claim 34 wherein the bioadhesive polymer of the bioadhesive layer comprises polyacrylic acid, sodium carboxymethyl cellulose or polyvinylpyrrolidone or a combination thereof.

38. The carrier device of claim 37 wherein the polyacrylic acid is partially crosslinked.

39. The carrier device of claim 27 wherein the non-bioadhesive backing layer comprises a pharmaceutically acceptable, film-forming, water-soluble polymer.

40. The carrier device of claim 39 wherein the pharmaceutically acceptable, fiim- forming, water-soluble polymer is hydroxyethyl cellulose, hydroxypropyi cellulose, hydroxypropyl methyl cellulose, hydroxyethylmethyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, ethylene oxide-propylene oxide copolymers, or a combination thereof.

41 . A composition for buccal or sublingual application comprising a distribution of multilayer microparticles in a base, wherein phenylephrine or a pharmaceutically acceptable salt thereof is adsorbed within the layers of the microparticies so as to be progressively released over time to the buccal or sublingual mucosa.

42. The composition of claim 41 in the form for application by means of a spray, mousse or drench. 2008/085523

44

43. The composition of claim 41 comprising a distribution of multiiayer microparticies in a soluble solid or gel base, the base material being formulated to dissolve within the mouth and liberate the microparticies to allow for contact of the microparticies with the mucous membranes of the oral cavity.

5

44. Composition of claim 41 wherein multilayer microparticies are selected to exhibit good adhesion to the mucous membranes of the ora! cavity.

45. The composition of claim 41 wherein the multilayer microparticies are in the 0 range 0.1-10 microns.

46. The composition of claim 41 wherein the multilayer microparticies comprise an aerosolized spray. 5

47. The composition according to claim 41 wherein the microparticies generally comprise polar structures with a positive surface charge.

48. The composition according to claim 1 further comprising additional active ingredients chosen from the group consisting of antihistamines, antibacterials,0 anti-inflammatory agents, and analgesic compounds,

49. The composition of claim 48 wherein the antihistamine is chosen from the group consisting of diphenhydramine, chlorpheniramine, tripelennamine, promethazine, clemastine, doxylamine, astemizole, terfenadsne, loratadine,5 desloratadine, cimetadine, famotidine, nizatidine, ranitidine, cromolyn and combinations thereof.

50. Composition according to claim 1 further comprising one or more lubricating and/or moisturising oils.

j 51. The composition of claim 50 wherein the lubricating and/or moisturising oils are selected from the group consisting of hyaluronic acid or sodium hyaiuronique, glycerol calendula officinalis flower extract or glycerin extract, guar hydroxypropyltrimoniurn chloride, xanthan gum, cellulose gum, sodium chtoride, olive oil, sunflower oil, almond oil, sesame oil, aloe vera, aloe barbadensis_s and combinations thereof.

52. A drug delivery device adapted for application sublingual^ of the oral cavity for fast release thereon of a composition comprising phenylephrine or a pharmaceutically acceptable sait thereof, said device comprising a body having the composition distributed therein and having a size and shape suitable for sublingual application

53. The device of claim 52 wherein the body is in the form of a tablet, a softgel capsule, a fast dissolving film.

54. The devise of claim 53 wherein the tablet is a fast dissolving or fast melting tablet

55. A pharmaceutical formulation adapted for application and adherence to the mucosa of the oral cavity for sustained release thereon of a composition comprising phenylephrine or a pharmaceutically acceptable salt thereof wherein the composition is in the form of a liquid or semisolid.

56. The pharmaceutical formulation of claim 55 wherein the liquid or semisolid congeals after application to oral mucosa.